NZ286340A

NZ286340A - Amides of 2-(4-indolyl piperazia-1-yl)-1-ph-enyl (and bemzyl)ethyl amine derivatives with various (cyclo) alkane carboxylic acids; pharmaceutical compositions

Info

Publication number: NZ286340A
Application number: NZ286340A
Authority: NZ
Inventors: John Patrick Yardley; Horace Fletcher
Original assignee: American Home Prod
Priority date: 1995-04-10
Filing date: 1996-04-10
Publication date: 1997-06-24
Also published as: AU5052296A; ZA962821B; CA2173693A1; IL117858A0; NO961404L; BR9601295A; US5519025A; MX9601326A; NO961404D0; CZ102896A3; EP0737677A1; JPH08283262A; SK45196A3; KR960037677A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £86340 286340 Priority Date(s): AS.l.ftl.JB.S. Complete Specification Filed: Class: Publication Date:. P.O. Journal No: /iillll NO DRAWINGS Patents Form No. 5 Our Ref: JB206234 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION 4-INDOLYLPIPERAZINYL DERIVATIVES We, AMERICAN HOME PRODUCTS CORPORATION, a Delaware Corporation, USA of Five Giralda Farms, Madison, New Jersey 07940-0874, United States Of America hereby declare the invention, for which We pray that a patent may be granted to us and the method by which it is to be performed, to be particularly descri^e^^f^smd by the following statement: PT05 683 32 - 1 - 'followed by page la) - to- 286340 AHP-94198 4-INDQLYLPIPERAZINYL DERIVATIVES Background of the Invention 5 US Patent 4,988,814 discloses a group of compounds in which the tertiary alkyl carboxylic acid acyl moiety appears. GB 2230781 discloses a group of 5-HTia antagonists which contain a heteroarylpiperazine moiety. In accordance with this invention there is provided a group of novel compounds which exhibit serotonin 5HTia activity which characterizes them as compounds capable of regulating various physiological functions and behavior including anxiety and affective states . In addition, 5-HTi-like antagonists, like those involved in the 15 present disclosure have been shown to be useful in inhibiting the growth of certain cancers, such as human prostatic carcinoma. Hence, the compounds of this invention are useful in the treatment of cancer. The compounds of the invention are of the following structure: Summary of the Invention 10 R2—C-CO 20 Formula I 25 in which R.1 is alkyl of 1 to 6 carbon atoms; R.2 and R^ are alkyl of 1 to 6 carbon atoms or taken together they are polymethylene of 2 to 12 carbon atoms; is hydrogen or alkyl of 1 to 6 carbon atoms; r5 is phenyl, benzyl, substituted phenyl, or substituted benzyl in which the substituents are hydroxy, halo, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, nitro, cyano, alkoxycarbonyl of 2 to 7 carbon atoms, (followed by paQQ 2) -2- 2 8 6 3 4 0 AHP-94198 amino or dialkylamino in which each alkyl group contains 1 to 6 carbon atoms; or a pharmaceutical^ acceptable salt thereof. 5 The halogen substituent referred to above may be chlorine, bromine, fluorine or iodine, fluorine being preferred. The pharmaceutically acceptable salts are derived from known inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, toluene sulfonic, naphthalenesulfonic, formic, acetic, propionic, oxalic, succinic, glycollic, lactic, malic, 10 tartaric, citric, ascorbic, maleic, hydroxymaleic, pyruvic, phenylacetic, benzoic, para-amino benzoic, para-hydroxybenzoic, salicylic, sulfanilic acids, and the like. The compounds of this invention contain a chiral center, providing for various stereoisomeric forms of the compounds such as racemic mixtures as well as the IS individual optical isomers, which isomers can be either prepared directly by asymmetric or stereospecific synthesis or by conventional separation of epimers or optical isomers from the racemic mixture. Examples of alkyl as a group or part of a group, e.g. arylalkyl, alkoxy or 20 alkanoxycarbonyl are straight or branched chains of 1-6 carbon atoms, preferably 1-4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl and n-butyl. The preferred compounds are those of the (R) configuration in which R* is alkyl of 1 to 3 carbon atoms, R^ and R^ are alkyl of 1 to 3 carbon atoms or taken 25 together they are polymethylene of 3 to 7 carbon atoms, R4 is hydrogen and R^ is phenyl or benzyl, or a pharmaceutically acceptable salt thereof. This invention also provides processes for preparing the compound of Formula (I) comprising: 30 a) acylation of a compound of Formula (E) with a compound of Formula (F) or a reactive derivative thereof, ' V,.* , * C E xt. 396 -3- 2 8 6^40 AHP-94198 R< R» /\ / \ nh2 ch2-n n v_y R1 fl2—c —co2H r V5 / \ R2-C—CONH CH2'N, R3 I b) converting a basic compound of Formula (I) to an acid addition or quartnary ammonium salt thereof, or vice versa, or c) resolving a mixture of isomeric compounds of Formula (I)to isolate a specific enantiomeric form substantially in the absence of the other isomers. The compounds of Formula (E) can be prepared by a sequence beginning with 10 the reaction of 4-indolyl-piperazine (B) with an N-protected aminoacid (A) in the presence of a coupling reagent such as l.l'-carbonyldiimidazole, iso-butylchloroformate, diethylcyanophosphonate or a carbodiimide, to give the N-protected aminoacid amide (C). The protecting group for the aminoacid is of the urethane type, particularly useful are those in which is tertiarybutyloxycarbonyl 15 (removable by acid) or benzyloxycaibonyl (removable by hydrogenation or by HBr). -4- 28 6 3 4 0 AHP-94198 I D After deprotection of (C) the aminoacid amide may be reduced to (E) using either diborane or LiAlH4. t 286340 AHP-94198 -5- Acylation with a carboxylic acid of Formula (F) affords the compounds of the invention having Formula (I), as described above. R1 R1 R2-C—C02H + E —•- R2-C - CONH ch2- Nv j* R3 R3 F I 5 Examples of suitable acylating derivatives include the acid halides (e.g. acid chlorides), azides, anhydridesv imidazolides (e.g. obtained from carbonyldiimidazole) or o-acylureas (e.g. obtained from a carbodiimide). 10 The compounds of this invention possess high affinity for the serotonin 5- HT ia receptor, and consequently, they are useful as antidepressant and anxiolytic agents for the treatment of a variety of central nervous system disorders such as depression, anxiety, sleep disorders, sexual dysfunction, alcohol and cocaine addiction, cognition enhancement and related problems. In addition, the compounds of 15 this invention show marked selectivity for the 5-HTi a receptors as opposed to the ai receptors. High affinity for the serotonin 5-HTia receptor was established by testing the claimed compound's ability to displace [3H] 8-OHDPAT (dipropylaminotetralin) from 20 the 5-HTia serotonin receptors in rat hippocampal membrane homogenate following the procedure of B. S. Alexander and M. D. Wood, J. Pharm. Pharmacol. 1988, 40. 888-891. The compound of Example 1, for example, as representative of the other compounds of the invention, exhibited an IC50 of 4.33 nM while the (S) isomer in Example 2 exhibited an IC50 binding potency at 35.5 nM. 25 Based upon this receptor binding data, the compounds of this invention are characterized as anxiolytic and/or antidepressant agents useful in the treatment of depression and in alleviating anxiety . As such, the compounds may be administered neat or with a pharmaceutical carrier to a patient in need thereofr^lfB&^armaceutical 30 carrier may be solid or liquid. ^ <r r V'j7 Mitt 19® -6- 2 8 6 3 4 0 AHP-94198 Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintergrating agents or an encapsulating material. 5 In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, 10 magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. Liquid carriers may be used in preparing solutions, suspensions, emulsions, 15 syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening 20 agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols ami polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated 25 coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions 30 can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form. Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities^the; 35 ingredient; the unit dosage forms can be packaged compositions, for e/arhple packetetl^ t 28 u 3 4 0 15 AHP-94198 -7- powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. 5 The dosage to be used in the treatment of a specific patient suffering from depression or anxiety must be subjectively determined by the attending physician. The variables involved include the specific state of anxiety or depression, and the size, age and response pattern of the patient. 10 The following examples are presented, without limitation on the scope of the invention claimed hereinafter, to illustrate the preparation of representative members of the compounds of the invention. Example 1 (R)-l-Methvl-cvclohexanecarboxvlic acid f2-r4-indolvn-plperazin-l-vll- 1-phenvl-ethvn-amide Benzyloxycarbonyl-Ji-phenylglycine (2.36 g, 0.0083 mol), and N-20 methylmorpholine (0.84 g, 0.0083 mol) were stirred in 100 mL of methylene chloride at -15 °C under a nitrogen atmosphere as isobutylchloroformate (1.13 g, 0.0083 mol) was added. After 15 minutes, 4-piperazmylindole (1.33 g, 0.0075 mol) was added and the mixture was stirred as it reached room temperature over 20 hours. The solution was washed with water (2 x), saturated NaHCC>3 (2 x) and dried over anhydrous 25 Na2SC>4. Evaporation of solvent left 3.6 g of product as a gum which was stirred in 30% HBr in acetic acid (100 mL) at room temperature for 30 minutes. Diethyl ether (300 mL) was added and the hydrobromide salt was filtered, washed with diethyl ether, and dried in vacuo overnight. The salt was shaken in 1 N NaOH and the amine was extracted with methylene chloride (3 x). The extracts were washed with water, dried 30 over anhydrous Na2S04, and evaporated to a gum, yield 1.6 g (57.6% from cbz-H-phenylglycine). (R)(l-Phenylglycyl)-4-(4-indolyl)piperazine (1.6g, 4.92 mmol) ai ^ aluminum hydride (0.81 g, 21.7 mmol) were refluxed in THF (500 nlL>-overnig_„^ 35 under nitrogen. The cooled reaction was quenched with IN NaOH (^02 mL), stirred t 2 8 6 5 4ft 25 AHP-94198 8- for 30 minutes, filtered, and the filtrate was evaporated. The residue was dissolved in ethyl acetate, washed with water, then brine, and dried (Na2SC>4). Evaporation of the solvent left (R)-2-(4-indolyl)-piperazin-l-yl-l-phenyl-ethylamine (1.39 g). Yield 88%. The IR spectrum was devoid of carbonyl peaks. Mass spectrum, EIM+.M/H 320. 5 1 -Methylcyclohexanecarbonyl chloride (Beilstein 918,9II10) prepared from 1-methylcyclohexane-carboxylic acid (0.75 g, 0.0052 mol) and thionyl chloride (0.76 mL, 0.010 mol) was added to a solution of the ethyl amine derivative prepared in the preceding paragraph (1.5 g, 0.0047 mol). Diisopropylethylamine (0.87 mL, 0.005 10 mol) in 50 mL of methylene chloride was also added. After 2 hours the solution was washed with water, saturated NaHC03, dried over anhydrous Na2SC>4 and evaporated. The product was crystallized from ethyl acetate/hexane. MP 132-134 °C. Rf 0.63 silica, EtOAc/hexane 1:1. IR 1652 cm"*. *H NMR (DMSO-d6): 5 1.08 (s, 3H), 1.1-1.5 (m, 10 H), 2.58-2.65 (m, 2H), 2.7-2.78 (m, 2H), 3.0-3.17 (m, 4H), 15 6.35 (t, 1H), 6.4 (d, 1H), 6.95-6.98 (s, 1H), 6.99-7.02 (d, 1H), 7.19-7.22 (t, 2H), 7.3-7.45 (m, 4H), 7.6-7.64 (d, 1H). The base was converted to the hydrochloride salt in ethyl acetate and precipitated by adding diethyl ether to provide the dihydrochloride, quarter hydrate. MP 206-208 °C. [a]D25-36.6, c=l%EtOH. 20 Analytical: C28H36N4O2 HC1-1/4 H2O. Calc'd: C, 64.42; H, 7.43; N, 10.73; CI, 13.58. Found: C, 64.37; H, 7.44; N, 10.43; CI, 13.55. Example 2 (S)-l-Methvl-cvclohexanecarboxvlic acid (2-r4-indolvll-piperazin-l.vll- l-phsnyl-ethyP-amWe Following the procedure of Example 1, with the exception that 30 benzyloxycarbonyl-L-phenylglycine is employed as the initial reactant provides the title compound as the dihydrochloride, 1/4 hydrate, mp - 185 - 190#C. Elemental analysis: C28H36N4O2 HCM/4 H2O. Calc'd: C, 64.42; H, 7.43; N, 10.73 35 Found: C, 64.59; H. 7.78; N, 10.39 ° „ 7 1396 L I 28 6 5 4 G AHP-94I98 -9- Example 3 fR)-l-Methvl-cvclohexanecarboxvlic acid f2-r4-indolvn-piDerazin-l-vll- Tert. butoxycarbonyl-£)-phenylalanine (2.65g, 0.01 mol) and N-methyl morpholine (1.11 mL, 0.01 mol) were stirred in methylene chloride (150 mL) at -15 °C as isobutyl chloroformate (1.3 mL, 0.01 mol) was added dropwise. After 15 minutes, 10 4-piperazinylindole (2.01 g, 0.01 mol) was added and the mixture was stirred as it reached room temperature over 20 hours. The solution was washed with water, sat. NaHC03, dried (anhyd. Na2S04) and evaporated. Yield 4.47 g, 100%. Mass spectrum EI M+ 448. The product was stirred in methylene chloride (50 mL) and trifluoroacetic acid (50 mL) at room temperature for 1 1/2 hours and evaporated. The 15 residue was shaken with IN NaOH and methylene chloride (2 x 100 mL). The organic layer was washed with water and dried (anhyd. Na2S04). Evaporation of the solvent left the base as an oil. Yield 3.5 g, 100%. Mass spectrum EI M+ 348. The base (3.4 g, 0.0097 mol) and lithium aluminum hydride (1.52 g, 0.04 mol) were refluxed in tetrahydrofuran (500 mL) overnight. The cooled reaction was quenched with IN 20 NaOH (9.1 mL) and filtered. The filtrate was evaporated and the residue was dissolved in ethyl acetate which was washed with water, then brine, dried (anhyd. Na2S04) and evaporated. Yield 3.0 g, 89.7%. Mass spectrum CI (M+H)+ 335. The amine (3.0 g, 0.0087 mol), diisopropyl ethyl amine (1.16 g, 0.0087 mol) and 1-methylcyclohexanecarbonyl chloride (1.41 g, 0.0088 mol) were stirred in 25 tetrahydrofuran (100 mL) at room temperature for 72 hours. The solution was evaporated and the residue was shaken with water and ethyl acetate. The ethyl acetate layer was washed with sat. NaHC03 then brine and dried (anhyd. Na2S04). Yield 3.05 g, 76.2%. The product was chromatographed on a silica dry column using chloroform/methanol, 99:1 as eluent. Yield 1.5 g. Mass spectrum EI M+ 458. The 30 base was converted to dihydrochloride in ethyl acetate with 3.6 N HC1 in ethyl acetate and dilution with diethyl ether followed by recrystallization from hot ethyl acetate to provide the dihydrochloride, sesquihydrate. IR 1650 cm~l. *H NMR (DMSO-d6): 8 0.9 - 0.94 (s, 3H), 1.0-1.37 (m, 10H), 1.8-2.4 (t, 2H), 2.81-2.92 (m, 1H), 2.95-3.02 (m, 1H), 3.14-3.2 (t, 1H), 3.22-3.45 (m, 8H),3.45-3.55 (d, 1H), 3.57-3.71 (mVv2H), 35 4.55-4.61 (m, 1H), 6.43 (s, 1H), 6.52-6.55 (d, 1H), 6.95-7 5 l-fDhenvlmethvlt-ethvlamide </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 2 8 6 5 4 0 AHP-94198 - 10- 1H), 7.17-7.2 (dd, IH), 7.25-7.5 (s, 5H), 7.6-7.65 (d, IH), 10.8-10.92 (s, IH), 11.15 (s, IH). Analytical: Calc'd: Found: C29H38N4O 2 HC1* 1.5 H2O C, 62.35; H, 7.76; N, 10.03 C.62.31; H, 7.72; N, 9.67 2 8 6 /> 4 o AHP-94198 - 11 - WHAT l/WE CLAIM IS CLAIMS

1. A compound of formula (I): I in which Rl is alkyl of 1 to 6 carbon atoms; R2 and R^ are alkyl of 1 to 6 carbon atoms or taken together they are polymethylene of 2 to 12 carbon atoms; R^ is hydrogen or alkyl of 1 to 6 carbon atoms; R5 is phenyl, benzyl, substituted phenyl, or substituted benzyl in which the substituents are hydroxy, halo, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, nitro, cyano, alkoxycarbonyl of 2 to 7 carbon atoms, amino or dialkylamino in which each alkyl group contains 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.

2. A compound of Claim 1, of the (R) configuration in which R* is alkyl of 1 to 3 carbon atoms, R^ and R^ are alkyl of 1 to 3 carbon atoms or taken together they are polymethylene of 3 to 7 carbon atoms, R4 is hydrogen and is phenyl or benzyl, or a pharmaceutically acceptable salt thereof.

3. A compound of Claim 1 which is 1-methyl-cyclohexanecarboxylic acid (2-[4-indolyl]-piperazin-l-yl]-l-phenyl-ethyl)-amide or a pharmaceutically acceptable salt thereof.

4. The compound of Claim 1 which is (R)-1-methyl-cyclohexanecarboxylic acid (2-[4-indolyl]-piperazin-l-yl]-l-phenyl-ethyl)-amide or a pharmaceutically acceptable salt thereof - 12- 2 8 6 3 AHP-94198

5. The compound of Claim 1 which is (S)-1-methyl-cyclohexanecarboxylic acid (2-[4-indolyl]-piperazin-1 -yl]- l-phenyl-ethyl)-amide or a pharmaceutically acceptable salt thereof.

6. A compound of Claim 1 which is 1-methyl-cyclohexanecarboxylic acid (2-[4-indolyl]-piperazin-l-yl]-l-(phenylmethyl)-ethylamide or a pharmaceutically acceptable salt thereof.

7. The compound of Claim 1 which is (R)-1-methyl-cyclohexanecarboxylic acid (2-[4-indolyl]-piperazin-l-yl]-l-(phenylmethyl)-ethylamide or a pharmaceutically acceptable salt thereof.

8. A method for the preparation of a compound of Formula (I) according to any one of claims 1 to 7 comprising: a) the acylation of a compound of Formula (E) with a compound of Formula (F) or a reactive derivative thereof + R2_q co H F R1 I E I 286340 - 13- wherein R* is alkyl of 1 to 6 carbon atoms; R2 and R3 are alkyl of 1 to 6 carbon atoms or taken together they are polymethylene of 2 to 12 carbon atoms; R4 is hydrogen or alkyl of 1 to 6 carbon atoms; R^ is phenyl, benzyl, substituted phenyl, or substituted benzyl in which the substituents are hydroxy, halo, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, nitro, cyano, alkoxycarbonyl of 2 to 7 carbon atoms, amino or dialkylamino in which each alkyl group contains 1 to 6 carbon atoms; b) converting the compound of Formula (I) to an acid addition or quarternary ammonium salt, or vice versa, or c) resolving a mixture of isomeric compounds of Formula (I) to isolate a specific enantiomeric form substantially in the absence of the other isomers.

9. A method for the preparation of a compound of Formula (E) comprising: a) reacting a 4-indolyl-piperazine of Formula (B) with an N-protected aminoacid of Formula (A) in the presence of a coupling reagent to give an N-protected aminoacid ainide of Formula (C) -14- wherein is alkyl of 1 to 6 carbon atoms; R.2 and are alkyl of 1 to 6 carbon atoms or taken together they are polymethylene of 2 to 12 carbon atoms; r4 is hydrogen or alkyl of 1 to 6 carbon atoms; R5 is phenyl, benzyl, substituted phenyl, or substituted benzyl in which the substituents are hydroxy, halo, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, nitro, cyano, alkoxycarbonyl of 2 to 7 carbon atoms, amino or dialkylamino in which each alkyl group contains 1 to 6 carbon atoms; b) deprotecting the compound of Formula (C) to produce the corresponding aminoacid amide of Formula (D) and c) reducing the aminoacid amide of formula (D) to produce the compound of Formula (E)

10. The use of a compound according to any one of claims 1 to 7 in the preparation of an anxiolytic, an antidepressant or an anticancer pharmaceutical. tN r © 18 APR I®7 28634 - 15 -

11. A compound as claimed in claim 1 as specifically set forth herein.

12. A process for producing a compound as claimed in claim 1 substantially as herein described with references to the Examples. AMERICAN HOME PRODUCTS CORPORATION Its Attorneys ALDWIN SON and CAREY end of clams </div>